This contract combines a basic research emphasis and the molecular biology expertise of the group at the Division of Molecular Virology, Georgetown University, with the continuous programmatic monitoring and direction of DMID staff towards inclusion of state- of-the-art protocols from outside researchers which would otherwise not be achievable at a grant-funded level. The basic research focus continues to be the characterization of the Woodchuck Hepatitis Virus (WHV) infection as a model for human hepatitis B virus (HBV) infection and its long-term sequelae. New parameters of immunology, pathogenesis, and virology will be addressed during the contract period. Studies on the human hepatitis D virus (HDV) which coinfects WHV-infected woodchucks will be expanded to include potential vaccine studies as well as pathogenic analyses of different human HDV isolates. The differences between the Ground Squirrel Hepatitis Virus (GSHV) and WHV will be examined to identify genetic causes of variation in disease progression. The eventual goal from all these studies is to discern what determinants of viral infection lead to disease chronicity as opposed to disease recovery and where can interdiction take place to prevent the events leading to cirrhosis and hepatocellular carcinoma in hepatitis B patients.